Stereospecificity of enzyme reactions

Virtually all biological reactions are stereospecific. This generalization applies not only to the enzyme-catalyzed reactions of intermediary metabolism, but also to the processes of nucleic acid synthesis and to the process of translation, in which the amino acids are linked in specific sequence to form the peptide chains of the enzymes. This review will be restricted mainly to some of the more elementary aspects of the stereospecificity of enzyme reactions, particularly to those features of chirality which have been worked out with the help of isotopes. 

Chiral methyl chiral lactic acid (5). This labeled molecule, useful for study of stereospecificity of enzymic reactions, has been prepared in a way that allows for synthesis of all 12 possible isomers. One key step is the stereospecific debromination of 1, accomplished by conversion to the vinyl-palladium cr-complex 2 followed by cleavage with CF3COOT to give the tritium-labeled 3. The next step is the catalytic deuteration of 3, accomplished with a rhodium(I) catalyst complexed with the ligands norbornadiene and (R)-l,2-bis(diphenylphosphino)propane. This reaction gives 4 with an optical purity of 81%. The product is hydolyzed to 5, which is obtained optically pure by cr3rstallization. 

Communicated in writing) Dr. Eley s review of enzyme catalysis made only brief reference to the very marked stereospecificity of enzyme reactions. Adsorption of substrates on enzymic proteins cannot account satisfactorily for this unless there is at least a two-point chemisorption throughout the whole of the reaction process. 

Stereospecificity of enzyme reactions , in Progress in Stereochemistry (Butterworths Scientific Publications, London), 1954, p. 318. 

Popjak, G. Stereospecificity of Enzyme Reactions. In Boyer, P. D., ed.. The Enzymes, 3rd ed., Vol. 2, Kinetics and Mechanism. New York Academic Press, 1970. [A review of stereochemical aspects of the citric acid cycle.]... 

Battersby and his group have recently reported the details of an extensive study of biogenetic interrelations among tetrahydroprotoberberines, benzophenanthridines, rhoeadines, and phthalideisoquinolines. A key step in this study of the stereospecificity of enzyme reactions was the use of horse liver alcohol dehydrogenase to prepare the complementary R- and 5-benzyl alcohols shown. These tritiated materials were needed for the synthesis of chirally labeled scoulerine. 

During the last two decades, the mechanisms of many enzymic processes have been established, and model systems have been developed that effectively mimic their action. In particular, the roles of thiamin, NAD, pyridoxal, flavins, Bl2, ferridoxin, and metals in many enzymic processes now are understood. Model systems have been developed to imitate the action of decarboxylases and esterases, to imitate the action of enzymes in binding their substrates, and to approach the stereospecificity of enzymes. Our laboratory recently has found phosphorylating agents that release monomeric methyl metaphosphate, which in turn carries out phosphorylation reactions, including some at carbonyl oxygen atoms, that suggest the actions of ATP. The ideas of biomimetic chemistry are illustrated briefly in terms of the processes mentioned above. 

Finally, if enzymes can be stabilized in the presence of organic solvents by immobilization, an area that appears especially promising is the synthesis of organic flavor compounds. This is likely to require regeneration of expensive cosubstrates, such as the nicotinamide coenzymes, and such processes remain to be optimized. However, the stereospecificity of enzyme-catalyzed reactions and the high... 

Concurrently with the development of research dealing with the stereochemical course of substitution at chiral phosphorus centers, the question of the stereospecificities of enzymes for metal-nucleotide complexes has also been addressed. The methodologies developed for the two types of studies differed initially, but significant overlap has appeared. The applications of the two approaches have unmasked the complete stereochemical courses of several phosphotransferase reactions. 

As shown in the catalytic reactions, the formation reactions and others, the asymmetric reactions of synthetic polypeptides are characterized by the participation of specific secondary structures. Such influence of the secondary conformation on the asymmetric reaction is considered to have a general importance in relation not only to the stereospecificity of the reaction of enzyme, but also to a possible way by which present-day enzymes obtained their high stereospecificity in the ctxirse of chemical evolution. 

Since 1980 several reviews have touched on the area of biohydrogenations7-17. The main incentive for choosing enzymatic methods for the hydrogenation of double bonds is to exploit the characteristic stereospecificity of enzymatic reactions. Thus, chiral products are obtained if the double bond of the substrate molecule is properly substituted. Such chiral products may be useful building blocks for the syntheses of chiral compounds. Further advantages of enzyme-catalyzed reactions are their high reaction specificity and rcgiospecificity as W ell as the mild reaction conditions under which they proceed. 

The importance of obstruction (steric hindrance) in determining the stereochemical course of enzymic reactions is further illustrated by a comparison of the stereospecificities of the alcohol dehydrogenases from yeast and from horse liver. The enzymes from both sources are A-side (re face) specific dehydrogenases wherein the pro-(R) hydrogen at C-l of the alcohol is in the transferring position Eq. (2)] ... 

Catalytic antibodies - These interesting molecules are antibodies with a very specific binding site to the transition state of an enzymatic reaction. The resulting molecules, called abzymes, act like antibodies. In some cases, abzymes can speed up reaction rates as much as lO -fold over the uncatalyzed reaction. The stereospecificity of enzymes (including abzymes) may provide a tremendous aid to the synthesis of stereospecific compounds in organic chemistry. 

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